Targeting cardiac resident CCR2+ macrophage-secreted MCP-1 to attenuate inflammation after myocardial infarction.

After myocardial infarction (MI), cardiac resident CCR2+ macrophages release various cytokines and chemokines, notably monocyte chemoattractant protein-1 (MCP-1). MCP-1 is instrumental in recruiting CCR2+ monocytes to the damaged region. The excessive arrival of these monocytes, which then become macrophages, perpetuates inflammation at the site of injury. This continuous inflammation leads to adverse tissue remodeling and compromises cardiac function over time. We hypothesized that neutralizing the MCP-1 secreted by cardiac resident CCR2+ macrophages can mitigate post-MI inflammation by curtailing the recruitment of monocytes and their differentiation into macrophages. In this work, we developed nanoparticles that target the infarcted heart, specifically accumulating in the damaged area after intravenous (IV) administration, and docking onto CCR2+ macrophages. These nanoparticles were designed to slowly release an MCP-1 binding peptide, HSWRHFHTLGGG (HSW), which neutralizes the upregulated MCP-1. We showed that the HSW reduced monocyte migration, inhibited pro-inflammatory cytokine upregulation, and suppressed myofibroblast differentiation in vitro. After IV delivery, the released HSW significantly decreased monocyte recruitment and pro-inflammatory macrophage density, increased cardiac cell survival, attenuated cardiac fibrosis, and improved cardiac function. Taken together, our findings support the strategy of MCP-1 neutralization at the acute phase of MI as a promising way to alleviate post-MI inflammation. STATEMENT OF SIGNIFICANCE: After a myocardial infarction (MI), CCR2+ macrophages resident in the heart release various cytokines and chemokines, notably monocyte chemoattractant protein-1 (MCP-1). MCP-1 is instrumental in attracting CCR2+ monocytes to the damaged region. The excessive arrival of these monocytes, which then become macrophages, perpetuates inflammation at the site of injury. This continuous inflammation leads to adverse tissue remodeling and compromises cardiac function over time. In this work, we tested the hypothesis that neutralizing the MCP-1 secreted by cardiac CCR2+ macrophages can mitigate post-MI inflammation by curtailing the recruitment of monocytes.